Is cyclobenzaprine (a muscle relaxant) safe to use during pregnancy, particularly in a female patient with a history of musculoskeletal issues or fibromyalgia?

Cyclobenzaprine Safety in Pregnancy

Cyclobenzaprine should be avoided during pregnancy, particularly in the first trimester and late third trimester, due to emerging evidence of potential birth defects and serious fetal complications, despite its FDA Pregnancy Category B classification.

FDA Classification and Official Guidance

The FDA labels cyclobenzaprine as Pregnancy Category B, stating that "reproduction studies have been performed in rats, mice and rabbits at doses up to 20 times the human dose, and have revealed no evidence of impaired fertility or harm to the fetus due to cyclobenzaprine" 1. However, the label explicitly notes that "there are no adequate and well-controlled studies in pregnant women" and recommends that "this drug should be used during pregnancy only if clearly needed" 1.

Recent Human Evidence Raises Significant Concerns

Birth Defect Associations

A large 2023 case-control study combining data from 33,615 cases and 13,110 controls found substantially elevated risks for multiple structural birth defects with periconceptional cyclobenzaprine exposure 2:

• Cleft palate: OR = 4.79 (95% CI 1.71-13.44)
• Anorectal atresia/stenosis: OR = 6.91 (95% CI 1.67-28.65)
• D-transposition of the great arteries: OR = 6.97 (95% CI 2.17-22.36)
• Coarctation of the aorta: OR = 5.58 (95% CI 1.88-16.58)
• Pulmonary valve stenosis: OR = 4.55 (95% CI 1.10-18.87)
• Cleft lip: OR = 2.50 (95% CI 0.89-7.02)
• Secundum atrial septal defect: OR = 3.08 (95% CI 0.83-11.45) 2

While the authors note these estimates are unadjusted and should be interpreted cautiously due to small numbers, the consistency of elevated risks across multiple cardiac and craniofacial defects is concerning 2.

Late Pregnancy Complications

A 2014 case report documented persistent pulmonary hypertension of the newborn (PPHN) and premature ductal closure in an infant whose mother used cyclobenzaprine during late pregnancy 3. The proposed mechanism involves cyclobenzaprine's inhibition of norepinephrine and serotonin reuptake, which can suppress prostaglandin and nitric oxide—factors critical for maintaining ductal patency 3. This represents a potentially life-threatening complication similar to risks seen with NSAIDs in the third trimester.

Safer Alternatives for Musculoskeletal Pain

First-Line Options

Acetaminophen is the preferred analgesic throughout all trimesters of pregnancy, used by 40-65% of pregnant women with an established safety profile 4, 5, 6. It should be used at the lowest effective dose for the shortest duration necessary 5, 6.

Short-Term NSAID Use (First and Second Trimester Only)

If acetaminophen is insufficient, nonselective NSAIDs with short half-lives (such as ibuprofen) may be used for 7-10 days maximum in the first and second trimester only 4, 5, 6. NSAIDs must be completely discontinued after gestational week 28 due to risks of oligohydramnios and premature ductus arteriosus closure 7, 4, 6.

Corticosteroids for Severe Inflammation

For severe radicular pain or inflammation, oral prednisone or prednisolone can be considered, as they are not associated with increased major birth defects when used appropriately 5, 6. If used, doses should be tapered to ≤5 mg/day when possible to minimize fetal exposure 5, 6.

Critical Clinical Considerations

Timing Matters

The first trimester (weeks 1-13) carries the highest teratogenic risk for structural malformations 6, 2. The third trimester poses risks for ductal closure and pulmonary hypertension 3.

Breastfeeding Concerns

Because cyclobenzaprine is closely related to tricyclic antidepressants (some of which are excreted in human milk), "caution should be exercised when cyclobenzaprine hydrochloride is administered to a nursing woman" 1.

Common Pitfall to Avoid

Do not rely solely on the FDA Pregnancy Category B designation as reassurance of safety. This classification is based on animal studies, and the recent human data suggest potential risks that were not apparent in animal models 1, 2. The absence of adequate human studies at the time of FDA classification does not equate to proven safety.

Clinical Algorithm

1. For pregnant patients with musculoskeletal pain:

   • Start with acetaminophen at lowest effective dose 4, 5, 6
   • Add physical therapy, heat/cold therapy, and positioning modifications

2. If acetaminophen insufficient and patient is <28 weeks gestation:

   • Consider short-term (7-10 days) ibuprofen at lowest dose 4, 5, 6
   • Reassess after short course

3. If severe inflammatory component:

   • Consider prednisone/prednisolone, taper to ≤5 mg/day when possible 5, 6

4. Avoid cyclobenzaprine entirely:

   • Risk of birth defects in first trimester 2
   • Risk of ductal closure and PPHN in third trimester 3
   • Insufficient human safety data throughout pregnancy 1

If inadvertent exposure to cyclobenzaprine occurs in early pregnancy, immediate referral to a maternal-fetal medicine specialist or genetics counselor is warranted 7.